Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression

Christopher M Rice, Luke C Davies, Jeff J Subleski, Nunziata Maio, Marieli Gonzalez-Cotto, Caroline Andrews, Nimit L Patel, Erika M Palmieri, Jonathan M Weiss, Jung-Min Lee, Christina M Annunziata, Tracey A Rouault, Scott K Durum, Daniel W McVicar

Research output: Contribution to journalArticle (Academic Journal)

Abstract

Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit+ neutrophils subsets can engage in oxidative mitochondrial metabolism. With limited glucose supply, oxidative neutrophils use mitochondrial fatty acid oxidation to support NADPH oxidase-dependent ROS production. In 4T1 tumour-bearing mice, mitochondrial fitness is enhanced in splenic neutrophils and is driven by c-Kit signalling. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and T cell suppression when glucose utilisation is restricted. Consistent with these findings, peripheral blood neutrophils from patients with cancer also display increased immaturity, mitochondrial content and oxidative phosphorylation. Together, our data suggest that the glucose-restricted tumour microenvironment induces metabolically adapted, oxidative neutrophils to maintain local immune suppression.

Original languageEnglish
Pages (from-to)5099
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 30 Nov 2018

Keywords

  • Animals
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Cells, Cultured
  • Flow Cytometry
  • Immunoblotting
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Mitochondria/metabolism
  • Neutrophils/metabolism
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Oxidative Stress
  • Reactive Oxygen Species/metabolism
  • Signal Transduction/physiology

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  • Cite this

    Rice, C. M., Davies, L. C., Subleski, J. J., Maio, N., Gonzalez-Cotto, M., Andrews, C., Patel, N. L., Palmieri, E. M., Weiss, J. M., Lee, J-M., Annunziata, C. M., Rouault, T. A., Durum, S. K., & McVicar, D. W. (2018). Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression. Nature Communications, 9(1), 5099. https://doi.org/10.1038/s41467-018-07505-2